title: Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3-dioxygenase with therapeutic activity in Lewis lung cancer (LLC) tumor-bearing mice.
abstract: Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO-1 inhibitor by screening of indole-based structures. Three series of 13 tryptanthrin derivatives were synthesized, and the structure-activity analysis was undertaken. The optimization led to the identification of 5c, which exhibited the inhibitory activity at a nanomolar level. In vitro 5c dramatically augmented the proliferation of T cells. When administered to Lewis lung cancer (LLC) tumor-bearing mice, 5c significantly inhibited IDO-1 activity and suppressed tumor growth. In addition, 5c reduced the numbers of Foxp3(+) regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University , Handan Road 220, Shanghai 200433, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Yang
authors.forename: Xishuai
authors.initials: X
authors.lastname: Li
authors.forename: Fangfang
authors.initials: F
authors.lastname: Hu
authors.forename: Yinlong
authors.initials: Y
authors.lastname: Li
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yang
authors.forename: Junkai
authors.initials: J
authors.lastname: Yan
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Kuang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011799:Quinazolines; C046243:tryptanthrine